成体干细胞移植在啮齿类关节炎关节中的肿瘤形成。
Tumor Formation of Adult Stem Cell Transplants in Rodent Arthritic Joints.
机构信息
Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University, 725 Welch Rd, Rm 1665, Stanford, CA, 94305-5654, USA.
Department of Pathology, Stanford University, Stanford, CA, USA.
出版信息
Mol Imaging Biol. 2019 Feb;21(1):95-104. doi: 10.1007/s11307-018-1218-7.
PURPOSE
While imaging matrix-associated stem cell transplants aimed for cartilage repair in a rodent arthritis model, we noticed that some transplants formed locally destructive tumors. The purpose of this study was to determine the cause for this tumor formation in order to avoid this complication for future transplants.
PROCEDURES
Adipose-derived stem cells (ADSC) isolated from subcutaneous adipose tissue were implanted into 24 osteochondral defects of the distal femur in ten athymic rats and two immunocompetent control rats. All transplants underwent serial magnetic resonance imaging (MRI) up to 6 weeks post-transplantation to monitor joint defect repair. Nine transplants showed an increasing size over time that caused local bone destruction (group 1), while 11 transplants in athymic rats (group 2) and 4 transplants in immunocompetent rats did not. We compared the ADSC implant size and growth rate on MR images, macroscopic features, histopathologic features, surface markers, and karyotypes of these presumed neoplastic transplants with non-neoplastic ADSC transplants.
RESULTS
Implants in group 1 showed a significantly increased two-dimensional area at week 2 (p = 0.0092), 4 (p = 0.003), and 6 (p = 0.0205) compared to week 0, as determined by MRI. Histopathological correlations confirmed neoplastic features in group 1 with significantly increased size, cellularity, mitoses, and cytological atypia compared to group 2. Six transplants in group 1 were identified as malignant chondrosarcomas and three transplants as fibromyxoid sarcomas. Transplants in group 2 and immunocompetent controls exhibited normal cartilage features. Both groups showed a normal ADSC phenotype; however, neoplastic ADSC demonstrated a mixed population of diploid and tetraploid cells without genetic imbalance.
CONCLUSIONS
ADSC transplants can form tumors in vivo. Preventive actions to avoid in vivo tumor formations may include karyotyping of culture-expanded ADSC before transplantation. In addition, serial imaging of ADSC transplants in vivo may enable early detection of abnormally proliferating cell transplants.
目的
在对啮齿动物关节炎模型中的软骨修复进行成像基质相关干细胞移植时，我们注意到一些移植形成了局部破坏性肿瘤。本研究的目的是确定这种肿瘤形成的原因，以便避免将来的移植出现这种并发症。
方法
从皮下脂肪组织中分离出脂肪来源的干细胞（ADSC），并将其植入 10 只去胸腺大鼠和 2 只免疫功能正常的对照大鼠的 24 个股骨远端骨软骨缺损中。所有移植均在移植后 6 周内进行连续磁共振成像（MRI）监测关节缺损修复。9 个移植随着时间的推移逐渐增大，导致局部骨破坏（第 1 组），而 11 个在去胸腺大鼠中的移植（第 2 组）和 4 个在免疫功能正常的大鼠中的移植没有。我们比较了这些疑似肿瘤性移植与非肿瘤性 ADSC 移植的 MRI 上 ADSC 移植大小和生长率、大体特征、组织病理学特征、表面标志物和核型。
结果
第 1 组在第 2 周（p=0.0092）、第 4 周（p=0.003）和第 6 周（p=0.0205）的 MRI 上显示出明显增加的二维面积，与第 0 周相比，第 1 组的植入物显示出明显增加的大小、细胞密度、有丝分裂和细胞学异型性，与第 2 组相比。第 1 组中有 6 个移植被确定为恶性软骨肉瘤，3 个移植为纤维粘液样肉瘤。第 2 组和免疫功能正常的对照组的移植显示出正常的软骨特征。两组均表现出正常的 ADSC 表型；然而，肿瘤性 ADSC 表现出二倍体和四倍体细胞的混合群体，没有遗传失衡。
结论
ADSC 移植可在体内形成肿瘤。避免体内肿瘤形成的预防措施可能包括在移植前对培养扩增的 ADSC 进行核型分析。此外，对体内 ADSC 移植的连续成像可以实现对异常增殖细胞移植的早期检测。
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